The Wnt pathway has an established role in human neoplasms, such as the pediatric renal cancer called Wilms' tumor, colorectal cancer, pancreatic cancer, lung cancer, prostate cancer, leukemia, and other cancers. Additionally, aberrations in the Wnt pathway have been reported to be involved in metastasis of cancer (e.g., prostate cancer), especially to bone.
The Wnt pathway has many members and interacts with a variety of signaling pathways. For example, the Disheveled (Dvl) family proteins (Dsh in Drosophila) are membrane-proximal signaling intermediates in the Wnt pathway. Downstream of Dvl is the enzyme GSK3β, a serine-threonine kinase that is a negative regulator of insulin and Wnt signaling. In the absence of a Wnt signal, GSK3β phosphorylates β-catenin and induces its ubiquitination and proteolytic degradation. The presence of a Wnt signal inhibits GSK3β, which stabilizes β-catenin, allowing it to translocate to the nucleus, where it acts as an essential cofactor for Tcf/Lef-dependent transcription. β-catenin-Tcf/Lef induces transcription of important downstream target genes, such as c-myc and cyclin D1, many of which have been implicated in cancer.
Additionally, adenomatous polyposis coli (APC) tumor suppressor gene, which is mutated in about 80% of sporadic colorectal cancers, interacts with β-catenin. Mutations in APC lead to uncontrolled activation of β-catenin leading to cancer. Thus, Wnt signaling results in β-catenin accumulation and transcriptional activation of specific target genes that are normally activated during development and aberrantly activated during cancer.
Therefore, there is a desire to identify new antagonists of the Wnt pathway in order to investigate those interactions, as well as to provide more effective chemotherapies for tumors that depend upon Wnt signaling.